A. Field of the Invention
The present invention relates to the use of myeloid cell biomarkers for the differential diagnosis, prognosis, and monitoring of renal cell carcinoma (RCC) or colorectal cancer (CRC). The present invention furthermore relates to monitoring the effect of a treatment against renal cell carcinoma (RCC) or colorectal cancer (CRC), and establishing a prognosis of the outcome of the treatment of renal cell carcinoma (RCC) or colorectal cancer (CRC). The present invention furthermore relates to panels of cellular biomarkers for use in the above methods, in particular multicolor panels for measuring said biomarkers.
For the purposes of the present invention, all references as cited herein are incorporated by reference in their entireties.
B. Brief Description of Related Art
In Europe, renal cell carcinoma (RCC) ranks as the seventh most common malignancy in men, amongst whom there are 29,600 new cases each year (3.5% of all cancers). Among women, there are 16,700 cases a year (ranks twelfth or 2.3% of all cancers). RCC is rare before the age of 40, and above this age it is twice as common in men as in women. Incidence by age rises rapidly from less than 2 per 100,000/year in patients under 40 years old to 38 per 100,000/year in the age group 65-69 years, thereafter it increases to 46 per 100,000/year in those older than 75 years.
A total of 25-30% of patients with RCC displays overt metastases at initial presentation. About one third of patients with kidney cancer will develop metastatic disease over time. Thus, nearly 50-60% of all patients with RCC will eventually present with metastatic disease. Among those with metastatic disease, approximately 75% have lung metastases, 36% lymph node and/or soft tissue involvement, 20% bone involvement, and 18% liver involvement.
RCC is the most lethal carcinoma of the genitourinary tumors with a 65% five-year survival rate compared to the 82% and 100% five-year survival rate for bladder or prostate cancer respectively (US 1972-2001 data). European average survival rates at 5 years (up to 1999) after diagnosis (1990-1994) for kidney cancer were about 58%, and RCC was classified by several authors as a cancer with only moderate prognosis. Overall, RCC is fatal in nearly 80% of patients. This figure indicates a strong medical need for effective and early clinical follow-up and treatment for recurrences.
The American Joint Committee on Cancer (MCC) has established staging of RCC by TNM classification (Kidney. In: American Joint Committee on Cancer 2002, TNM Classification of renal cell carcinoma). The staging system for renal cell cancer is based on the degree of tumor spread beyond the kidney.
Survival strongly depends on the stage at which the tumor is diagnosed: 5-year survival is only 12% for patients bearing lesions with distant metastases, but 80% for those with localized malignancies.
Globally, colorectal carcinoma (CRC) is the third most common cancer. Colon and rectum cancer account for about 1 million new cases per year, and unlike as for most other tumors, numbers are not so different in men and women (ratio, 1.2:1). In Europe, CRC is the second most common cancer and the second most common cancer-related cause of death in both men and women with approx. 380,000 new cases and about 200,000 disease-related deaths per year. The raw incidence rate in 2002 for men and women was 88.3 and 84.0/100,000, respectively; the raw mortality was 34.8 and 35.2/100,000, respectively. These data clearly reflect the significance of CRC as an enormous source of both individual and societal burden. CRC is a cancer of the elderly population as the mean age at the time of disease manifestation in men and women is 69 and 75 years, respectively. Besides dietary and lifestyle factors (e.g. obesity, lack of physical exercise, smoking, regular alcohol consumption) other risk factors are familial occurrence of CRC, hereditary CRCs (familial adenomatous polyposis [FAP], attenuated FAP [attenuated adenomatous polyposis coli; AAPC], hereditary non-polyposis colorectal carcinoma [HNPCC], hamartomatous polyposis syndromes) and inflammatory bowel diseases such as ulcerative colitis or Crohn's disease.
CRC mostly occurs as adenocarcinoma of the mucous membranes in rectum, sigma, colon transversum/descendens, and colon ascendens/caecum. Early colorectal carcinoma may be cured by primary surgery. Distant metastases, however, spread to regional lymph nodes and to liver, lung, and other organs (such as CNS). Due to unspecific symptoms, CRC will often be diagnosed at a relatively late stage and approx. 25% of patients with CRC will have metastatic disease (mCRC) when first presented to their physicians. An additional 30% of newly diagnosed patients with localized resectable CRC will subsequently develop a metastatic recurrence.
Besides the Dukes' system, CRC is usually staged using the TNM system developed by the AJCC (latest revision in 2002), which compartmentalizes carcinomas according to the depth of invasion of the primary tumor, the absence or presence of regional lymph node metastases, and the absence or presence of distant metastases. As the possible number of resulting categories is very large, various categories are therefore grouped under Stages I through IV. Recently, Stage III was further subdivided into Stages IIIA to IIIC, since these were identified as significant independent prognostic covariates.
During the past three decades, cancer-related mortality has shown a continuous decrease. Meanwhile, the overall 5-year survival rate in men and women has increased to 63%. This survival increase may largely be attributed to improvements in surgical management, adjuvant therapy for localized high-risk disease, and the multimodality management of advanced metastatic disease.
Myeloid derived suppressor cells (MDSCs) is a term describing several cellular subsets of myeloid cells with immunosuppressive properties that have been discussed to be relevant in the biology of cancer immune editing.
Myeloid-derived suppressor cells (MDSC) contribute to immune dysfunctions induced by tumors both in experimental models and patients. In tumor-bearing mice, MDSC are phenotypically heterogeneous cells that vary in their surface markers, likely depending on soluble factors produced by different tumors at different stages of maturation, as well as in cancer patients that very efficiently suppress T cell function. It is known that a growing tumor stimulates myelopoiesis and affects cell differentiation through the production of growth factors and cytokines.
Lechner et al. (in: Lechner M G, Liebertz D J, Epstein A L. Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells. J. Immunol. 2010 Aug. 15; 185(4):2273-84. Epub 2010 Jul. 19) describe that in cancer patients, increased MDSCs correlate with more aggressive disease and a poor prognosis. Expression of 15 immune factors (TGFbeta, IL-1beta, IL-4, IL-6, IL-10, GM-CSF, M-CSF, IDO, fms-related tyrosine kinase 3 ligand, c-kit ligand, inducible NO synthase, arginase-1. TNF-alpha, cyclo-oxygenase 2, vascular endothelial growth factor [VEGF]) by MDSC-inducing human solid tumor cell lines were evaluated by RT-PCR. Based upon these data, cytokine mixtures were then tested for their ability to generate suppressive CD33(+) cells from healthy donor PBMCs in vitro by measuring their ability to inhibit the proliferation of, and IFN-gamma production by, fresh autologous human T cells after CD3/CD28 stimulation. The authors suggest that some cytokines are potential therapeutic targets for the inhibition of MDSC induction in cancer patients.
Allan (in Nature Reviews Immunology 8, 828, November 2008) describes that Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immune cells that accumulates in tumour-bearing hosts and in response to inflammation. Although it has been established that the capacity of MDSCs to inhibit T-cell responses prevents tumour rejection, the mechanisms that underlie MDSC accumulation and suppressor function are unclear.
Despite the above recent progresses in the diagnosis and management of RCC and CRC, still biological markers are needed that can be used to achieve an improved diagnosis, in particular a differential diagnosis, a prognosis, a monitoring of the effect, and an understanding of the best course of treatment of renal cell carcinoma (RCC) and/or colorectal cancer (CRC), in order to further improve the survival and to better adjust the treatment of people in need. Furthermore, the markers should also allow for a prognosis of the outcome of said treatment of renal cell carcinoma (RCC) or colorectal cancer (CRC). It is therefore an object of the present invention, to provide respective biological markers and diagnostic, prognostic and predictive methods.